Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure

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Abstract

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-α (TNF-α) and TNF-α soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 ± 1.9 years, New York Heart Association class 2.1 ± 0.3, left ventricular ejection fraction 31 ± 5%; mean ± SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 ± 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-α release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-α compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 ± 46 vs 22 ± 4 [p = 0.009], 149 ± 48 vs 34 ± 4 [p = 0.002], and 328 ± 88 vs 89 ± 16 pg/ml [p = 0.002], respectively; mean ± SEM). Patients with cardiac cachexia produced significantly less TNF-α compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-α and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.

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Study population

We studied 15 patients with HF (aged 65 ± 1.9 years, New York Heart Association class 2.1 ± 0.3, left ventricular ejection fraction 31 ± 5%; mean ± SEM) and 7 healthy control subjects of similar age (mean age 59 ± 5 years; Table 1). The patients were recruited from the Royal Brompton Heart Failure Clinic (London, United Kingdom) and diagnosed with HF based on appropriate clinical signs and symptoms, together with objective evidence of reduced left ventricular function (ejection fraction <40%).

Study population

There were no significant differences between patients and controls in terms of age, height, weight, and body mass index (all p >0.05; Table 1). When patients were subgrouped into subjects with or without cardiac cachexia, body mass index was significantly lower in the subjects with cardiac cachexia (22.2 ± 1.7 vs 28.2 ± 4.1, p <0.002). There were no other significant differences between the 2 groups.

Whole blood stimulation

Patients with HF demonstrated elevated TNF-α release in response to stimulation by endotoxin

Discussion

We have shown that endotoxin, at pathophysiologic concentrations found in advanced and decompensated HF, induces the production of TNF-α in a dose-dependent manner in patients with mild and moderate HF. The confirmatory finding of elevated mRNA would suggest that de novo synthesis of TNF-α contributes, at least in part, to this finding. The release of sTNFR2, an important prognostic marker of survival, was likewise enhanced.

No previous study has evaluated the effects of low concentrations of

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